Page 1 of 28. FAYOSIM (levonorgestrel and ethinyl estradiol tablets USP, and ethinyl estradiol tablets USP), for oral use Initial U.S.

Transcription

1 Page 1 of 28 HIGHLIGHTS OF PRESCRIBING INFORMATION These highlights do not include all the information needed to use FAYOSIM safely and effectively. See full prescribing information for FAYOSIM. FAYOSIM (levonorgestrel and ethinyl estradiol tablets USP, and ethinyl estradiol tablets USP), for oral use Initial U.S. Approval: 1982 WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS See full prescribing information for complete boxed warning. Women over 35 years old who smoke should not use Fayosim. (4) Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptive (COC) use. (4) RECENT MAJOR CHANGES Contraindications (4) 8/2017 Warnings and Precautions (5.4) 8/ INDICATIONS AND USAGE Fayosim are an estrogen/progestin COC indicated for use by women to prevent pregnancy (1) DOSAGE AND ADMINISTRATION Take one tablet daily by mouth at the same time every day for 91 days (2) Take tablets in the order directed on the Extended-Cycle wallet.(2) DOSAGE FORMS AND STRENGTHS Fayosim consist of 91 tablets in the following order (3): 42 pink tablets containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 white tablets containing 0.15 mg of levonorgestrel and mg ethinyl estradiol, and 21 light blue tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 mustard tablets containing 0.01 mg of ethinyl estradiol. (3) WARNINGS AND PRECAUTIONS Vascular risks: Stop Fayosim if a thrombotic event occurs. Stop Fayosim at least 4 weeks before and through 2 weeks after major surgery. Start Fayosim no earlier than 4 weeks after delivery, in women who are not breastfeeding. (5.1) Liver disease: Discontinue Fayosim if jaundice occurs. (5.2) High blood pressure: Do not prescribe Fayosim for women with uncontrolled hypertension or hypertension with vascular disease. (5.3) Carbohydrate and lipid metabolic effects: Monitor prediabetic and diabetic women taking Fayosim. Consider an alternate contraceptive method for women with uncontrolled dyslipidemias. (5.6) Headache: Evaluate significant change in headaches and discontinue Fayosim if indicated. (5.7) Uterine bleeding: Evaluate irregular bleeding or amenorrhea. (5.8) ADVERSE REACTIONS The most common adverse reactions ( 2%) in clinical trials for Fayosim were headaches, heavy/irregular vaginal bleeding, nausea/vomiting, acne, dysmenorrhea, weight increased, mood changes, anxiety/panic attack, breast pain and migraines (6). To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at or FDA at FDA-1088 or DRUG INTERACTIONS Drugs or herbal products that induce certain enzymes, including CYP3A4, may decrease the effectiveness of COCs or increase breakthrough bleeding. Counsel patients to use a back-up or alternative method of contraception when enzyme inducers are used with COCs. (7.1) USE IN SPECIFIC POPULATIONS Nursing Mothers: Not recommended for nursing mothers; can decrease milk production. (8.3) See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. Revised: November CONTRAINDICATIONS A high risk of arterial or venous thrombotic diseases (4) Undiagnosed abnormal uterine bleeding (4) Breast cancer or other estrogen- or progestin-sensitive cancer (4) Liver tumors or liver disease (4) Pregnancy (4) FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS 1. INDICATIONS AND USAGE 2. DOSAGE AND ADMINISTRATION 2.1 How to Take Fayosim 2.2 How to Start Fayosim 2.3 Advice in Case of Gastrointestinal Disturbances 3. DOSAGE FORMS AND STRENGTHS 4. CONTRAINDICATIONS 5. WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Disorders and Other Vascular Problems 5.2 Liver Disease 5.3 High Blood Pressure 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment 5.5 Gallbladder Disease 5.6 Carbohydrate and Lipid Metabolic Effects 5.7 Headache 5.8 Bleeding Irregularities 5.9 COC Use Before or During Early Pregnancy 5.10 Depression 5.11 Carcinoma of the Breast and Cervix 5.12 Effect on Binding Globulins 5.13 Monitoring 5.14 Hereditary Angioedema 5.15 Chloasma 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience 6.2 Postmarketing Experience 7. DRUG INTERACTIONS 7.1 Effects of Other Drugs on Combined Oral Contraceptives 7.2 Effects of Combined Oral Contraceptives on Other Drugs 7.3 Concomitant Use with Hepatitis C Vaccine (HCV) Combination Therapy - Liver Enzyme Elevation 7.4 Interference with Laboratory Tests 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy 8.3 Nursing Mothers 8.4 Pediatric Use 8.5 Geriatric Use 8.6 Hepatic Impairment 8.7 Renal Impairment 10. OVERDOSAGE 11. DESCRIPTION 12. CLINICAL PHARMACOLOGY 12.1 Mechanism of Action 12.2 Pharmacodynamics 12.3 Pharmacokinetics 13. NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14. CLINICAL STUDIES 16. HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied 16.2 Storage Conditions 17 PATIENT COUNSELING INFORMATION * Sections or subsections omitted from the full prescribing information are not listed.

2 FULL PRESCRIBING INFORMATION WARNING: CIGARETTE SMOKING AND SERIOUS CARDIOVASCULAR EVENTS Cigarette smoking increases the risk of serious cardiovascular events from combination oral contraceptives (COC) use. This risk increases with age, particularly in women over 35 years of age, and with the number of cigarettes smoked. For this reason, COCs should not be used by women who are over 35 years of age and smoke. [See CONTRAINDICATIONS (4)] 1 INDICATIONS AND USAGE Fayosim is indicated for use by females of reproductive age to prevent pregnancy. 2 DOSAGE AND ADMINISTRATION 2.1 How to Take Fayosim Instruct patients to take Fayosim once a day by mouth at the same time every day for 91 days. To achieve maximum contraceptive effectiveness, Fayosim must be taken exactly as directed and at intervals not exceeding 24 hours. For patient instructions regarding missed pills, see FDAapproved patient labeling. 2.2 How to Start Fayosim For each 91-day course, take in the following order: 1. Start the first pink tablet (0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol) on the first Sunday after the onset of menstruation. If menstruation begins on a Sunday, take the tablet on that day. Then take one pink tablet once a day for a total of 42 consecutive days. Use a non-hormonal back-up method of contraception (such as condoms and spermicide) for the first 7 days of treatment. 2. One white tablet (0.15 mg of levonorgestrel and mg ethinyl estradiol) once a day for 21 consecutive days. 3. One light blue tablet (0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol) once a day for 21 days. 4. One mustard tablet (0.01 mg of ethinyl estradiol) once a day for 7 days. Bleeding should occur during mustard tablet use. Begin the next and all subsequent 91-day courses of Fayosim without interruption on the same day of the week (i.e., Sunday) on which the patient began her first dose. Follow the same schedule as the initial 91-day course: pink tablet once a day for 42 days, white tablet once a day for 21 days, light blue tablet once a day for 21 days, and mustard tablet once a day for 7 days. If the patient does not immediately start her next pill pack, instruct her to protect herself from pregnancy by using a non-hormonal back-up method of contraception until she has taken a pink tablet daily for 7 consecutive days. If unscheduled spotting or bleeding occurs, instruct the patient to continue on the same regimen. If the bleeding is persistent or prolonged, advise the patient to consult her healthcare provider. For a postpartum woman who is not breastfeeding or after a second trimester abortion, start Fayosim no earlier than four weeks postpartum due to increased risk of thromboembolism. If the Page 2 of 28

3 patient starts on Fayosim postpartum and has not yet had a period, evaluate for possible pregnancy, and instruct her to use an additional method of contraception until she has taken a pink tablet for 7 consecutive days. Consider the possibility of ovulation and conception prior to initiation. 2.3 Advice in Case of Gastrointestinal Disturbances In case of severe vomiting or diarrhea, absorption may not be complete and additional contraceptive measures should be taken. If vomiting or diarrhea occurs within 3 to 4 hours after taking a pink, white or light blue tablet, handle this as a missed tablet [see FDA-approved patient labeling]. 3 DOSAGE FORMS AND STRENGTHS Fayosim (levonorgestrel and ethinyl estradiol tablets, and ethinyl estradiol tablets) are available as round, film-coated, biconvex tablets debossed with LU on one side, packaged in Extended- Cycle wallet, each containing a 13-week supply of tablets in the following order: 42 pink tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol: debossed with U19 on the other side 21 white tablets containing 0.15 mg of levonorgestrel and mg ethinyl estradiol: debossed with U20 on the other side 21 light blue tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with V21 on the other side and 7 mustard tablets containing 0.01 mg of ethinyl estradiol: debossed with V22 on the other side 4 CONTRAINDICATIONS Do not prescribe Fayosim to women who are known to have the following conditions: A high risk of arterial or venous thrombotic diseases. Examples include women who are known to: Smoke, if over age 35 [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)]. Have deep vein thrombosis or pulmonary embolism, now or in the past [see WARNINGS AND PRECAUTIONS (5.1)]. Have cerebrovascular disease [see WARNINGS AND PRECAUTIONS (5.1)]. Have coronary artery disease [see WARNINGS AND PRECAUTIONS (5.1)]. Have thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) [see WARNINGS AND PRECAUTIONS (5.1)]. Have inherited or acquired hypercoagulopathies [see WARNINGS AND PRECAUTIONS (5.1)]. Have uncontrolled hypertension [see WARNINGS AND PRECAUTIONS (5.3)]. Have diabetes with vascular disease [see WARNINGS AND PRECAUTIONS (5.6)]. Have headaches with focal neurological symptoms or have migraine headaches with or without aura if over age 35 [see WARNINGS AND PRECAUTIONS (5.7)]. Liver tumors, benign or malignant, or liver disease [see WARNINGS AND PRECAUTIONS (5.2) and USE IN SPECIFIC POPULATIONS (8.6)]. Undiagnosed abnormal uterine bleeding [see WARNINGS AND PRECAUTIONS (5.8)]. Page 3 of 28

4 Pregnancy, because there is no reason to use COCs during pregnancy [see WARNINGS AND PRECAUTIONS (5.9) and USE IN SPECIFIC POPULATIONS (8.1)]. Breast cancer or other estrogen- or progestin-sensitive cancer, now or in the past [see WARNINGS AND PRECAUTIONS (5.11)]. Use of Hepatitis C drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to the potential for ALT elevations [see WARNINGS AND PRECAUTIONS (5.4)]. 5 WARNINGS AND PRECAUTIONS 5.1 Thromboembolic Disorders and Other Vascular Problems Stop Fayosim if an arterial or deep venous thrombotic event (VTE) occurs. Stop Fayosim if there is unexplained loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions. Evaluate for retinal vein thrombosis immediately. If feasible, stop Fayosim at least 4 weeks before and through 2 weeks after major surgery or other surgeries known to have an elevated risk of VTE. Start Fayosim no earlier than 4 weeks after delivery, in women who are not breastfeeding. The risk of postpartum VTE decreases after the third postpartum week, whereas the risk of ovulation increases after the third postpartum week. The use of COCs increases the risk of VTE. However, pregnancy increases the risk of VTE as much or more than the use of COCs. The risk of VTE in women using COCs is 3 to 9 per 10,000 woman-years. The risk of VTE is highest during the first year of use of a COC. Data from a large, prospective cohort safety study of various COCs suggest that this increased risk, as compared to that in non-coc users, is greatest during the first 6 months of COC use. Data from this safety study indicate that the greatest risk of VTE is present after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC. The risk of thromboembolic disease due to COCs gradually disappears after COC use is discontinued. Use of Fayosim provides women with more hormonal exposure on a yearly basis than conventional monthly oral contraceptives containing the same strength synthetic estrogens and progestins (an additional 9 and 13 weeks of exposure to progestin and estrogen, respectively, per year). In the clinical trial, three cases of deep vein thrombosis were reported. Use of COCs also increases the risk of arterial thromboses such as strokes and myocardial infarctions, especially in women with other risk factors for these events. COCs have been shown to increase both the relative and attributable risks of cerebrovascular events (thrombotic and hemorrhagic strokes), although, in general, the risk is greatest among older (>35 years of age), and hypertensive women who also smoke. COCs also increase the risk for stroke in women with other underlying risk factors. Use COCs with caution in women with cardiovascular disease risk factors. Page 4 of 28

5 5.2 Liver Disease Impaired Liver Function Do not use Fayosim in women with acute viral hepatitis or severe (decompensated) cirrhosis of the liver [see CONTRAINDICATIONS (4)].Acute disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. Discontinue Fayosim if jaundice develops. Liver Tumors Fayosim is contraindicated in women with benign and malignant liver tumors [see CONTRAINDICATIONS (4)]. Hepatic adenomas are associated with COC use. An estimate of the attributable risk is 3.3 cases/100,000 COC users. Rupture of hepatic adenomas may cause death through intra-abdominal hemorrhage. Studies have shown an increased risk of developing hepatocellular carcinoma in long-term (> 8 years) COC users. However, the attributable risk of liver cancers in COC users is less than one case per million users. 5.3 High Blood Pressure Fayosim is contraindicated in women with uncontrolled hypertension or hypertension with vascular disease [see CONTRAINDICATIONS (4)]. For women with well-controlled hypertension, monitor blood pressure and stop Fayosim if blood pressure rises significantly. An increase in blood pressure has been reported in women taking COCs, and this increase is more likely in older women and with extended duration of use. The incidence of hypertension increases with increasing concentration of progestin. 5.4 Risk of Liver Enzyme Elevations with Concomitant Hepatitis C Treatment During clinical trials with the Hepatitis C combination drug regimen that contains obmitasvir/paritaprevir/ritonavir, with or without dasabuvir, ALT elevations greater than 5 times the upper limit of normal (ULN), including some cases greater than 20 times the ULN, were significantly more frequent in women using ethinyl estradiol-containing medications, such as COCs. Discontinue Fayosim prior to starting therapy with the combination drug regimen ombitasvir/paritaprevir/ritonavir, with or without dasabuvir [see CONTRAINDICATIONS (4)]. Fayosim can be restarted approximately 2 weeks following completion of treatment with the Hepatitis C combination drug regimen. 5.5 Gallbladder Disease Studies suggest a small increased relative risk of developing gallbladder disease among COC users. Use of COCs may also worsen existing gallbladder disease. A past history of COC-related cholestasis predicts an increased risk with subsequent COC use. Women with a history of pregnancy-related cholestasis may be at an increased risk for COCrelated cholestasis. Page 5 of 28

6 5.6 Carbohydrate and Lipid Metabolic Effects Carefully monitor prediabetic and diabetic women who are taking Fayosim. COCs may decrease glucose tolerance in a dose-related fashion. Consider alternative contraception for women with uncontrolled dyslipidemias. A small proportion of women will have adverse lipid changes while on COCs. Women with hypertriglyceridemia, or a family history thereof, may be at an increased risk of pancreatitis when using COCs. 5.7 Headache If a woman taking Fayosim develops new headaches that are recurrent, persistent, or severe, evaluate the cause and discontinue Fayosim if indicated. Consider discontinuation of Fayosim in the case of increased frequency or severity of migraine during COC use (which may be prodromal of a cerebrovascular event) [see CONTRAINDICATIONS (4)]. 5.8 Bleeding Irregularities Bleeding and/or spotting that occurs at any time while taking the first 84 tablets (pink, white and light blue) of each extended-cycle regimen is considered unscheduled bleeding/spotting. Bleeding that occurs during the time a woman takes the seven tablets (mustard) containing 10 mcg of ethinyl estradiol is considered scheduled bleeding. Unscheduled and Scheduled Bleeding and Spotting Unscheduled (breakthrough) bleeding and spotting sometimes occur in patients on COCs, especially during the first 3 months of use. If unscheduled bleeding persists or occurs after previously regular cycles on Fayosim, check for causes such as pregnancy or malignancy. If pathology and pregnancy are excluded, bleeding irregularities may resolve over time or with a change to a different COC. Before prescribing Fayosim, consider the occurrence of fewer scheduled menses (4 per year instead of 13 per year) against the occurrence of increased unscheduled bleeding and/or spotting. A 12- month open-label study of the efficacy of Fayosim in preventing pregnancy assessed scheduled and unscheduled bleeding [see CLINICAL STUDIES (14)] in 3,597 women who completed 34, day cycles of exposure. A total of 178 (4.9%) of the women discontinued Fayosim, at least in part, due to bleeding or spotting. Scheduled (withdrawal) bleeding and/or spotting remained fairly stable over time, with an average of 3 to 4 days of bleeding and/or spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting decreased over successive 91-day cycles. Table 1 below presents the number of days with unscheduled bleeding, spotting, and unscheduled bleeding and/or spotting in Treatment Cycles 1 to 4. Page 6 of 28

7 Table 1 Number of Unscheduled Bleeding, Spotting and Bleeding and/or Spotting Days per 91-day Cycle Cycle (N) Days of Unscheduled Bleeding per 84-Day Interval Median Days Per Subject- Month Mean Q1 Median Q3 1 (3330) (2820) (2433) (2213) Cycle (N) Days of Unscheduled Spotting per 84-Day Interval Median Days Per Subject- Month Mean Q1 Median Q3 1 (3330) (2820) (2433) (2213) Cycle (N) Days of Unscheduled Bleeding and/or Spotting per 84-Day Interval Median Days Per Subject- Month Mean Q1 Median Q3 1 (3330) (2820) (2433) (2213) Q1 = Quartile 1: 25% of women had this number of days of unscheduled bleeding/spotting Median: 50% of women had this number of days of unscheduled bleeding/spotting Q3 = Quartile 3: 75% of women had this number of days of unscheduled bleeding/spotting Figure 1 shows the percent of Fayosim subjects in the primary clinical trial with 7 days or 20 days of unscheduled bleeding and/or spotting, or just unscheduled bleeding, during each 91-day treatment cycle. Page 7 of 28

8 Figure 1: Percent of Women Taking Fayosim Who Reported Unscheduled Bleeding and/or Spotting Amenorrhea and Oligomenorrhea Women who are not pregnant and use Fayosim may experience amenorrhea. Based on data from the clinical trial, amenorrhea occurred in approximately 1.9% of women during Cycle 1, 7.7% during Cycle 2, 10.7% during Cycle 3, and 10.1% during Cycle 4 using Fayosim. Rule out pregnancy in the event of amenorrhea. Some women may experience amenorrhea or oligomenorrhea after stopping COCs, especially when such a condition was pre-existent. 5.9 COC Use Before or During Early Pregnancy Extensive epidemiological studies have revealed no increased risk of birth defects in women who have used oral contraceptives prior to pregnancy. Studies also do not suggest a teratogenic effect, particularly in so far as cardiac anomalies and limb-reduction defects are concerned, when taken inadvertently during early pregnancy. Discontinue Fayosim if pregnancy is confirmed. The administration of oral contraceptives to induce withdrawal bleeding should not be used as a test for pregnancy [see USE IN SPECIFIC POPULATIONS (8.1)] Depression Carefully observe women with a history of depression and discontinue Fayosim if depression recurs to a serious degree. Six cases of suicidality (suicide attempts and suicidal behavior) were reported in the clinical trial; several of these cases occurred in women with a psychiatric history Carcinoma of the Breast and Cervix Fayosim is contraindicated in women who currently have or have had breast cancer because breast cancer may be hormonally sensitive [see CONTRAINDICATIONS (4)]. There is substantial evidence that COCs do not increase the incidence of breast cancer. Although some past studies have suggested that COCs might increase the incidence of breast cancer, more recent studies have not confirmed such findings. Page 8 of 28

9 Some studies suggest that COCs are associated with an increase in the risk of cervical cancer or intraepithelial neoplasia. However, there is controversy about the extent to which these findings are due to differences in sexual behavior and other factors Effect on Binding Globulins The estrogen component of COCs may raise the serum concentrations of thyroxine-binding globulin, sex hormone-binding globulin and cortisol-binding globulin. The dose of replacement thyroid hormone or cortisol therapy may need to be increased Monitoring A woman who is taking COCs should have a yearly visit with her healthcare provider for a blood pressure check and for other indicated health care Hereditary Angioedema In women with hereditary angioedema, exogenous estrogens may induce or exacerbate symptoms of angioedema Chloasma Chloasma may occur with COC use, especially in women with a history of chloasma gravidarum. Advise women who tend to develop chloasma to avoid exposure to the sun or ultraviolet radiation while taking Fayosim. 6 ADVERSE REACTIONS The following serious adverse reactions with the use of COCs are discussed elsewhere in the labeling: Serious cardiovascular events and stroke [see BOXED WARNING and WARNINGS AND PRECAUTIONS (5.1)] Vascular events [see WARNINGS AND PRECAUTIONS (5.1)] Liver disease [see WARNINGS AND PRECAUTIONS (5.2)] Adverse reactions commonly reported by COC users are: Irregular uterine bleeding Nausea Breast tenderness Headache 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety data described below are from a 12-month, US, open-label study, which enrolled women aged 18 to 40, of whom 3,597 took at least one dose of Fayosim (2,661 woman-years of exposure) [see CLINICAL STUDIES (14)]. Page 9 of 28

10 Adverse Reactions Leading to Study Discontinuation 13.3% of the women discontinued from the clinical trial due to an adverse reaction; the most common adverse reactions ( 1% of women) leading to discontinuation were heavy/irregular bleeding (5.0%), mood swings/alteration/affect lability (1.4%), headaches/migraines (1.3%), weight increased (1.3%) and acne (1.0%). Common Adverse Reactions ( 2% of women) Headaches (12.2%), heavy/irregular vaginal bleeding (9.7%), nausea/vomiting (8.8%), acne (5.4%), dysmenorrhea (5.4%), weight increased (4.6%), mood changes (depression, depressed mood, crying, major depression, affective disorder, depression suicidal, dysthymic disorder) (2.9%), anxiety/panic attack (2.4%), breast tenderness/pain/discomfort (2.2%), migraine (2.0%). Serious Adverse Reactions ( 2 women) Abortion Spontaneous, Suicide Attempt, Cholecystitis/Cholelithiasis, Deep Vein Thrombosis, Ectopic Pregnancy. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of other extendedcycle COCs containing levonorgestrel and ethinyl estradiol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Gastrointestinal disorders Abdominal distension, vomiting General disorders and administration site conditions Chest pain, fatigue, malaise, edema peripheral, pain Immune system disorders Hypersensitivity reaction Investigations Blood pressure increased Musculoskeletal and connective tissue disorders Muscle spasms, pain in extremity Nervous system disorders Dizziness, loss of consciousness Psychiatric disorders Insomnia Reproductive and breast disorders Dysmenorrhea Page 10 of 28

11 Respiratory, thoracic and mediastinal disorders Pulmonary embolism, pulmonary thrombosis Skin and subcutaneous tissue disorders Alopecia Vascular disorders Thrombosis 7 DRUG INTERACTIONS Consult the labeling of concurrently-used drugs to obtain further information about interactions with hormonal contraceptives or the potential for enzyme alterations. No drug-drug interaction studies were conducted with Fayosim. 7.1 Effects of Other Drugs on Combined Oral Contraceptives Substances Diminishing the Efficacy of COCs Drugs or herbal products that induce certain enzymes, including cytochrome P450 3A4 (CYP3A4), may decrease the effectiveness of COCs or increase breakthrough bleeding. Some drugs or herbal products that may decrease the effectiveness of hormonal contraceptives include phenytoin, barbiturates, carbamazepine, bosentan, felbamate, griseofulvin, oxcarbazepine, rifampicin, topiramate and products containing St. John s wort. Interactions between oral contraceptives and other drugs may lead to breakthrough bleeding and/or contraceptive failure. Counsel women to use an alternative method of contraception or a back-up method when enzyme inducers are used with COCs, and to continue back-up contraception for 28 days after discontinuing the enzyme inducer to ensure contraceptive reliability. Substances Increasing the Plasma Concentrations of COCs Co-administration of atorvastatin and certain COCs containing EE increase AUC values for EE by approximately 20%. Ascorbic acid and acetaminophen may increase plasma EE concentrations, possibly by inhibition of conjugation. CYP3A4 inhibitors such as itraconazole or ketoconazole may increase plasma hormone concentrations. Human immunodeficiency virus (HIV)/ Hepatitis C Virus (HCV) Protease Inhibitors and Non-nucleoside Reverse Transcriptase Inhibitors Significant changes (increase or decrease) in the plasma concentrations of estrogen and progestin have been noted in some cases of co-administration with HIV/HCV protease inhibitors or with non-nucleoside reverse transcriptase inhibitors. Antibiotics There have been reports of pregnancy while taking hormonal contraceptives and antibiotics, but clinical pharmacokinetic studies have not shown consistent effects of antibiotics on plasma concentrations of synthetic steroids. Page 11 of 28

12 7.2 Effects of Combined Oral Contraceptives on Other Drugs COCs containing EE may inhibit the metabolism of other compounds. COCs have been shown to significantly decrease plasma concentrations of lamotrigine, likely due to induction of lamotrigine glucuronidation. This may reduce seizure control; therefore, dosage adjustments of lamotrigine may be necessary. Women on thyroid hormone replacement therapy may need increased doses of thyroid hormone because serum concentration of thyroid-binding globulin increases with use of COCs. 7.3 Concomitant Use with Hepatitis C Vaccine (HCV) Combination Therapy Liver Enzyme Elevation Do not co-administer Fayosim with HCV drug combinations containing ombitasvir/paritaprevir/ritonavir, with or without dasabuvir, due to potential for ALT elevations [see WARNINGS AND PRECAUTIONS (5.4)]. 7.4 Interference with Laboratory Tests The use of contraceptive steroids may influence the results of certain laboratory tests, such as coagulation factors, lipids, glucose tolerance, and binding proteins. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy There is little or no increased risk of birth defects in women who inadvertently use COCs during early pregnancy. Epidemiologic studies and meta-analyses have not found an increased risk of genital or non-genital birth defects (including cardiac anomalies and limb-reduction defects) following exposure to low dose COCs prior to conception or during early pregnancy. The administration of COCs to induce withdrawal bleeding should not be used as a test for pregnancy. COCs should not be used during pregnancy to treat threatened or habitual abortion. 8.3 Nursing Mothers When possible, advise the nursing mother to use other forms of contraception until she has weaned her child. COCs can reduce milk production in breastfeeding mothers. This is less likely to occur once breastfeeding is well established; however, it can occur at any time in some women. Small amounts of oral contraceptive steroids and/or metabolites are present in breast milk. 8.4 Pediatric Use Safety and efficacy of Fayosim have been established in women of reproductive age. Efficacy is expected to be the same for postpubertal adolescents under the age of 18 as for users 18 years and older. Use of Fayosim before menarche is not indicated. 8.5 Geriatric Use Fayosim has not been studied in women who have reached menopause and is not indicated in this population. Page 12 of 28

13 8.6 Hepatic Impairment No studies have been conducted to evaluate the effect of hepatic impairment on the disposition of Fayosim. However, steroid hormones may be poorly metabolized in patients with hepatic impairment. Acute or chronic disturbances of liver function may necessitate the discontinuation of COC use until markers of liver function return to normal and COC causation has been excluded. [See CONTRAINDICATIONS (4) and WARNINGS AND PRECAUTIONS (5.2)]. 8.7 Renal Impairment No studies have been conducted to evaluate the effect of renal impairment on the disposition of Fayosim. 10 OVERDOSAGE There have been no reports of serious ill effects from overdose of oral contraceptives, including ingestion by children. Overdosage may cause withdrawal bleeding in females and nausea. 11 DESCRIPTION Fayosim (levonorgestrel and ethinyl estradiol tablets USP, and ethinyl estradiol tablets USP) are an extended-cycle oral contraceptive. Fayosim consists of 42 pink tablets containing 0.15 mg levonorgestrel and 0.02 mg ethinyl estradiol, 21 white tablets containing 0.15 mg levonorgestrel and mg ethinyl estradiol, and 21 light blue tablets containing 0.15 mg levonorgestrel and 0.03 mg ethinyl estradiol, and 7 mustard tablets containing 0.01 mg ethinyl estradiol. Levonorgestrel is a progestin and ethinyl estradiol is an estrogen. The structural formulas, molecular formulas, molecular weights, and chemical names for the active components are shown below: Levonorgestrel is chemically 18,19-Dinorpregn-4-en-20-yn-3-one, 13-ethyl-17-hydroxy-(17α)-(- )-. Page 13 of 28

14 Ethinyl Estradiol is 19-Norpregna-1,3,5(10)-trien-20-yne-3,17-diol, (17α)-. Each pink tablet contains the following inactive ingredients: Anhydrous lactose, croscarmellose sodium, FD&C blue #1 aluminum lake, FD&C Red #40 aluminum lake, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and titanium dioxide. Each white tablet contains the following inactive ingredients: Anhydrous lactose, croscarmellose sodium, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and titanium dioxide. Each light blue tablet contains the following inactive ingredients: Anhydrous lactose, croscarmellose sodium, FD&C blue #1 aluminum lake, FD&C yellow #6 aluminum lake, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone and titanium dioxide. Each mustard tablet contains the following inactive ingredients: Anhydrous lactose, FD&C yellow #6 aluminum lake, hypromellose, iron oxide yellow, magnesium stearate, microcrystalline cellulose, polacrillin potassium, polyethylene glycol, polysorbate 80 and titanium dioxide. Ethinyl Estradiol Tablets USP meets USP Dissolution Test CLINICAL PHARMACOLOGY 12.1 Mechanism of Action COCs lower the risk of becoming pregnant primarily by suppressing ovulation. Other possible mechanisms may include cervical mucus changes that inhibit sperm penetration and endometrial changes that reduce the likelihood of implantation Pharmacodynamics No pharmacodynamic studies were conducted with Fayosim Pharmacokinetics Absorption Ethinyl estradiol and levonorgestrel are absorbed with maximum plasma concentrations occurring within 2 hours after Fayosim administration. Levonorgestrel is completely absorbed Page 14 of 28

15 after oral administration (bioavailability nearly 100%) and is not subject to first-pass metabolism. Ethinyl estradiol is absorbed from the gastrointestinal tract but, due to first-pass metabolism in gut mucosa and liver, the bioavailability of ethinyl estradiol is approximately 40%. The effect of food on the rate and the extent of levonorgestrel and ethinyl estradiol absorption following oral administration of Fayosim have not been evaluated. The mean plasma pharmacokinetic parameters of levonorgestrel following administration of another levonorgestrel/ethinyl estradiol combination tablet with an equal dose of levonorgestrel for 84 days, in healthy women are reported in Table 2. Table 2: Mean Pharmacokinetic Parameters for 150 mcg Levonorgestrel Following Administration of a Levonorgestrel/ethinyl estradiol Combination Tablet Once Daily for 84 Days AUC0 to 24 hr (mean ± SD) Cmax (mean ± SD) Tmax (mean ± SD) Day ± 6.1 ng hr/ml 3.0 ± 1.0 ng/ml 1.3 ± 0.4 hours Day ± 25.1 ng hr/ml 6.2 ± 1.6 ng/ml 1.3 ± 0.4 hours Day ± 24.6 ng hr/ml 5.5 ± 1.6 ng/ml 1.3± 0.3 hours Following repeated daily dosing of levonorgestrel/ethinyl estradiol oral contraceptives, levonorgestrel plasma concentrations accumulate more than predicted based on single-dose pharmacokinetics, due in part, to increased SHBG levels that are induced by ethinyl estradiol, and a possible reduction in hepatic metabolic capacity. Systemic exposure to ethinyl estradiol following administration of a LNG/EE combination tablet increases linearly in an approximate dose-proportional manner over the range of doses of 20 mcg to 30 mcg within this product. Systemic exposure to EE (as assessed by AUC) at steady state following administration of levonorgestrel/ethinyl estradiol oral contraceptives is approximately 20% higher than expected based on single-dose data for the dose range of 20 to 30 mcg. Distribution The apparent volume of distribution of levonorgestrel is reported to be approximately 1.8 L/kg. Levonorgestrel is about 97.5 to 99% protein-bound, principally to sex hormone binding globulin (SHBG) and, to a lesser extent, serum albumin. The apparent volume of distribution of ethinyl estradiol is reported to be approximately 4.3 L/kg. Ethinyl estradiol is about 95 to 97% bound to serum albumin. Ethinyl estradiol does not bind to SHBG, but induces SHBG synthesis, which leads to decreased levonorgestrel clearance. Metabolism Following absorption, levonorgestrel is conjugated at the 17β-OH position to form sulfate and to a lesser extent, glucuronide conjugates in plasma. Significant amounts of conjugated and unconjugated 3α,5β-tetrahydrolevonorgestrel are also present in plasma, along with much smaller amounts of 3α,5α-tetrahydrolevonorgestrel and 16β-hydroxylevonorgestrel. Levonorgestrel and its phase I metabolites are excreted primarily as glucuronide conjugates. Page 15 of 28

16 Metabolic clearance rates may differ among individuals by several-fold, and this may account in part for the wide variation observed in levonorgestrel concentrations among users. First-pass metabolism of ethinyl estradiol involves formation of ethinyl estradiol-3-sulfate in the gut wall, followed by 2-hydroxylation of a portion of the remaining untransformed ethinyl estradiol by hepatic cytochrome P-450 3A4 (CYP3A4). Levels of CYP3A4 vary widely among individuals and can explain the variation in rates of ethinyl estradiol hydroxylation. Hydroxylation at the 4-, 6-, and 16- positions may also occur, although to a much lesser extent than 2-hydroxylation. The various hydroxylated metabolites are subject to further methylation and/or conjugation. Excretion About 45% of levonorgestrel and its metabolites are excreted in the urine and about 32% are excreted in feces, mostly as glucuronide conjugates. The mean terminal elimination half-life for levonorgestrel after a single dose of Fayosim ranged from 36 to 41 hours. Ethinyl estradiol is excreted in the urine and feces as glucuronide and sulfate conjugates, and it undergoes enterohepatic recirculation. The terminal elimination half-life of ethinyl estradiol following single doses of Fayosim is approximately 16.5 hours. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility [See WARNINGS AND PRECAUTIONS (5.2, 5.11) and USE IN SPECIFIC POPULATIONS (8.1)]. 14 CLINICAL STUDIES In a 12-month, multicenter, open-label, single-arm clinical trial conducted in the US, 3,667 women, 18 to 40 years old, were enrolled and 3,565 were treated for up to four 91-day cycles, which equates to thirteen 28-day cycles, to assess the safety and efficacy of Fayosim, completing the equivalent of 33, day cycles of exposure. The racial demographic of those treated was: Caucasian (64%), African-American (19%), Hispanic (11%), Asian (2%), and Other (3%). There were no exclusions for body mass index (BMI) or weight. The weight range of those women treated was 83 to 402 lbs., with a mean weight of lbs. Among the women in the trial, 44% were current hormonal contraceptive users, 39% were prior users (who had used hormonal contraceptives in the past), and 17% were new starters. Of treated women, 13.2% were lost to follow-up, 12.8% discontinued due to an adverse event, and 6.1% discontinued by withdrawing their consent. The pregnancy rate (Pearl Index [PI]) in women aged 18 to 35 years was 3.19 pregnancies per 100 woman-years of use (95% confidence interval 2.49, 4.03), based on 70 pregnancies that occurred after the onset of treatment and up to and including 7 days after the last pill. Cycles in which conception did not occur, but which included the use of backup contraception, were not included in the calculation of the PI. The PI includes patients who did not take the drug correctly. Page 16 of 28

17 16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Fayosim (levonorgestrel and ethinyl estradiol tablets USP, and ethinyl estradiol tablets USP) are available in Extended-Cycle Wallets each containing a 13-week supply of tablets in the following order: 42 pink, round, biconvex film-coated tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol: debossed with LU on one side and U19 on the other side 21 white, round, biconvex film-coated tablets, containing 0.15 mg of levonorgestrel and mg ethinyl estradiol: debossed with LU on one side and U20 on the other side 21 light blue, round, biconvex film-coated tablets, containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol: debossed with LU on one side and V21 on the other side 7 mustard, round, biconvex film-coated tablets, containing 0.01 mg of ethinyl estradiol: debossed with LU on one side and debossed with V22 on the other side They are supplied as follows: 1 extended cycle wallet of 91 tablets which is packed in a pouch (NDC ). Such one pouch is packed in a carton (NDC ). 2 extended cycle wallets of 91 tablets each which is packed in a pouch (NDC ). Such two pouches are packed in a carton (NDC ) Storage Conditions Store at 25 C (77 F); excursions permitted to 15 to 30 C (59 to 86 F) [see USP Controlled Room Temperature]. 17 PATIENT COUNSELING INFORMATION See FDA-approved patient labeling (Patient Information). Counsel patients on the following information: Cigarette smoking increases the risk of serious cardiovascular events from COC use, and that women who are over 35 years old and smoke should not use COCs. Increased risk of VTE compared to non-users of COCs is greatest after initially starting a COC or restarting (following a 4-week or greater pill-free interval) the same or a different COC. Fayosim does not protect against HIV-infection (AIDS) and other sexually transmitted infections. The Warnings and Precautions associated with COCs. Fayosim is not to be used during pregnancy; if pregnancy occurs during use of Fayosim, instruct the patient to stop further intake. Take one tablet daily by mouth at the same time every day. Instruct patients what to do in the event pills are missed. See WHAT TO DO IF YOU MISS PILLS section of FDA- Approved Patient Labeling. Use a back-up or alternative method of contraception when enzyme inducers are used with COCs. Page 17 of 28

18 COCs may reduce breast milk production. This is less likely to occur if breastfeeding is well established. Women who start COCs postpartum, and who have not yet had a period, should use an additional method of contraception until they have taken a pink tablet for 7 consecutive days. Amenorrhea may occur. Consider pregnancy in the event of amenorrhea, and rule out pregnancy if amenorrhea is associated with symptoms of pregnancy, such as morning sickness or unusual breast tenderness. Distributed by: Lupin Pharmaceuticals, Inc. Baltimore, Maryland United States Manufactured by: Lupin Limited Pithampur (M.P.) INDIA November 2017 ID#: Page 18 of 28

19 FDA-Approved Patient Labeling Guide for Using Fayosim [levonorgestrel and ethinyl estradiol tablets USP (0.15 mg/0.02 mg, 0.15 mg/0.025 mg and 0.15 mg/0.03 mg), and ethinyl estradiol tablets USP (0.01 mg)] WARNING TO WOMEN WHO SMOKE Do not use Fayosim if you smoke cigarettes and are over 35 years old. Smoking increases your risk of serious cardiovascular side effects from birth control pills, including death from heart attack, blood clots or stroke. This risk increases with age and the number of cigarettes you smoke. Birth control pills help to lower the chances of becoming pregnant. They do not protect against HIV infection (AIDS) and other sexually transmitted infections. What is Fayosim? Fayosim is a birth control pill. It contains two female hormones, an estrogen called ethinyl estradiol and a progestin called levonorgestrel. How Well Does Fayosim Work? Your chance of getting pregnant depends on how well you follow the directions for taking your birth control pills. The more carefully you follow the directions, the less chance you have of getting pregnant. Based on the results of a single clinical study lasting 12 months, 2 to 4 women out of 100 women may get pregnant during the first year they use Fayosim. The following chart shows the chance of getting pregnant for women who use different methods of birth control. Each box on the chart contains a list of birth control methods that are similar in effectiveness. The most effective methods are at the top of the chart. The box on the bottom of the chart shows the chance of getting pregnant for women who do not use birth control and are trying to get pregnant. Page 19 of 28

20 How Do I Take Fayosim? 1. Take one pill every day at the same time. Take pills in the order directed on the Extended- Cycle wallet. Do not skip pills or delay taking your pills. If you miss pills (including starting the pack late), you could get pregnant. The more pills you miss, the more likely you are to get pregnant. 2. You may have spotting or light bleeding, or feel sick to your stomach during the first few months of taking Fayosim. If you feel sick to your stomach, do not stop taking the pill. The problem will usually go away. If it doesn't go away, check with your healthcare provider. If you vomit or have diarrhea within 4 hours after taking your pill, follow the instructions in What To Do If You Miss Pills. 3. Missing pills can also cause spotting or light bleeding, even when you take the missed pills later. On the days you take 2 pills to make up for missed pills, you could also feel a little sick to your stomach. 4. If you have trouble remembering to take Fayosim, talk to your healthcare provider about how to make pill-taking easier or about using another method of birth control. Page 20 of 28

21 Before you start taking Fayosim 1. Decide what time of day you want to take your pill. It is important to take it at about the same time every day. 2. Look at your Extended-Cycle Tablet Wallet. Your Extended-Cycle Tablet Wallet consists of 3 blister strips that hold 91 individually sealed pills (a 13-week or 91-day cycle). The 91 pills consist of 42 pink tablets, each containing 0.15 mg of levonorgestrel and 0.02 mg ethinyl estradiol, 21 white tablets containing 0.15 mg of levonorgestrel and mg ethinyl estradiol, 21 light blue tablets containing 0.15 mg of levonorgestrel and 0.03 mg ethinyl estradiol, and 7 mustard tablets containing 0.01 mg of ethinyl estradiol. Blister strip 1 contains 4 rows of 7 pink pills. Page 21 of 28

22 Blister strip 2 contains 2 rows of 7 pink pills (a total of 14 pink pills) followed by 2 rows of 7 white pills (a total of 14 white pills). Page 22 of 28

23 Blister strip 3 contains 1 row of 7 white pills, followed by three rows of 7 light blue pills (a total of 21 light blue pills), followed by the last row, which contains 7 mustard pills. 3. Also find: Where on the first blister strip in the pack to start taking pills (upper left corner at the start arrow) and In what order to take the pills (follow the weeks and arrow). 4. Be sure you have another kind of birth control (such as condoms and spermicides) ready at all times, to use as a back-up in case you miss pills. When to Start Fayosim 1. Take the first pink pill on the Sunday after your period starts, even if you are still bleeding. If your period begins on Sunday, start the first pink pill that same day. 2. Use another method of birth control (such as condoms and spermicides) as a back-up method if you have sex anytime from the Sunday you start your first pink pill until the next Sunday (first 7 days). If you have been using a different hormonal method of birth control (such as a different pill, the patch, or the vaginal ring ), you need to use another method of birth control (such as condoms and spermicides) each time you have sex after stopping your old method of birth control until you have taken Fayosim for 7 days. 3. If you have recently given birth and have not yet had a period, use another method of birth control if you have sex (such as condoms and spermicides) as a back-up method until you have taken Fayosim for 7 days. Page 23 of 28

24 How to Take Fayosim 1. Take one pill at the same time every day until you have taken the last pill in the Extended- Cycle wallet. Do not skip pills even if you are experiencing spotting or bleeding or feel sick to your stomach (nausea). Do not skip pills even if you do not have sex very often. Do not skip the mustard pills because they are not placebo pills ( sugar pills ). They contain ethinyl estradiol. 2. When you finish a Wallet After taking the last mustard pill, start taking the first pink pill from a new Extended- Cycle Wallet the very next day (this should be on a Sunday) regardless of when your period started. 3. If you miss your scheduled period when you are taking the mustard pills, contact your healthcare provider because you may be pregnant. If you are pregnant, you should stop taking Fayosim. What To Do If You Miss Pills If you MISS 1 pink, white or light blue pill: 1. Take it as soon as you remember. Take the next pill at your regular time. This means you may take 2 pills in 1 day. 2. You do not need to use a back-up birth control method if you have sex. If you MISS 2 pink, white or light blue pills in a row: 1. Take 2 pills on the day you remember, and 2 pills the next day. 2. Then take 1 pill a day until you finish the pack. 3. You could become pregnant if you have sex in the 7 days after you miss two pills. You MUST use another birth control method (such as condoms and spermicide) as a back up for the 7 days after you restart your pills. If you MISS 3 OR MORE pink, white or light blue pills in a row: 1. Do not take the missed pills. Keep taking 1 pill every day as indicated on the pack until you have completed all of the remaining pills in the pack. For example: If you resume taking the pill on Thursday, take the pill under Thursday and do not take the missed pills. You may experience bleeding during the week following the missed pills. 2. You could become pregnant if you have sex during the days of missed pills or during the first 7 days after restarting your pills. 3. You MUST use a non-hormonal birth control method (such as condoms and spermicide) as a back-up when you miss pills and for the first 7 days after you restart your pills. If you do not have your period when you are taking the mustard pills, call your healthcare provider because you may be pregnant. If you MISS ANY of the 7 mustard colored pills: 1. Take the next scheduled pill at the scheduled time. 2. You do not need a back-up method of birth control. Page 24 of 28